Abstract

Dyskinesia is a serious motor complication caused by prolonged administration of l-DOPA to patients affected by Parkinson's disease. Accumulating evidence indicates that l-DOPA-induced dyskinesia (LID) is primarily caused by the development of sensitized dopamine D1 receptor (D1R) transmission in the medium spiny neurons (MSNs) of the striatum. This phenomenon, combined with chronic administration of l-DOPA, leads to persistent and intermittent hyper-activation of the cAMP signaling cascade. Activation of cAMP signaling results in increased activity of the cAMP-dependent protein kinase (PKA) and of the dopamine- and cAMP-dependent phosphoprotein of 32 kDa (DARPP-32), which regulate several downstream effector targets implicated in the control of the excitability of striatal MSNs. Dyskinesia is also accompanied by augmented activity of the extracellular signal-regulated kinases (ERK) and the mammalian target of rapamycin complex 1 (mTORC1), which are involved in the control of transcriptional and translational efficiency. Pharmacological or genetic interventions aimed at reducing abnormal signal transduction at the level of these various intracellular cascades have been shown to attenuate LID in different animal models. For instance, LID is reduced in mice deficient for DARPP-32, or following inhibition of PKA. Blockade of ERK obtained genetically or using specific inhibitors is also able to attenuate dyskinetic behavior in rodents and non-human primates. Finally, administration of rapamycin, a drug which blocks mTORC1, results in a strong reduction of LID. This review focuses on the abnormalities in signaling affecting the D1R-expressing MSNs and on their potential relevance for the design of novel anti-dyskinetic therapies.

Schematic diagram illustrating some of the major abnormalities related to sensitized D1R-signaling and associated to LID. In PD, the loss of striatal dopamine leads to sensitization of D1Rs on the striatonigral MSNs of the direct pathway. Emerging evidence indicates that, if persistent, this phenomenon results in the appearance of dyskinesia. D1R sensitization may be caused by augmented D1R expression at the cell surface. Chronic administration of l-DOPA promotes the release of BDNF from corticostriatal neurons, leading to activation of TrκB receptors and increased expression of D3Rs, specifically in striatonigral MSNs. Direct interaction with D3Rs is likely to increase the levels of membrane-bound D1Rs, thereby exacerbating D1R sensitization and dyskinetic behavior. In line with this possibility, D3R antagonists have been found to counteract LID in experimental models of PD. Sensitized D1R transmission may also be caused by increased levels of adenylyl cyclase 5 (AC 5) in striatonigral MSNs. Increased responsiveness of the D1R/Gαolf/AC5 machinery to l-DOPA results in augmented synthesis of cAMP and hyper-activation of PKA and DARPP-32. Pharmacological inhibition of PKA, or genetic inactivation of DARPP-32 have been shown to reduce LID. Abnormal PKA/DARPP-32 signaling increases the phosphorylation of GluR1. This effect promotes the excitability of MSNs and may participate in the loss of corticostriatal LTD and depotentiation associated to LID. Sensitized D1R-mediated transmission leads also to activation of ERK, which controls transcriptional and translational processes. Both pharmacological and genetic suppression of ERK signaling counteracts the development and expression of LID. In the nucleus, PKA/DARPP-32 and ERK/MSK1 signaling leads to phosphorylation of CREB and histone H3, and increased expression of immediate early genes and prodynorphin. Reduced expression/activity of ΔfosB efficiently counteracts LID. Activation of ERK promotes mTORC1-dependent signaling, thereby accelerating mRNA translation. Blockade of mTORC1 with rapamycin has been found to attenuate the development of LID. Red color indicates receptors or signaling components whose targeting reduces LID. See text for abbreviations.

Targeting signaling upstream and downstream of ERK in LID. The abnormal activation of ERK produced by administration of l-DOPA in experimental models of PD is implicated in the emergence of dyskinetic behavior. ERK is activated by Ras-GRF1 and CalDAG-GEF II, which induce the exchange of GDP for GTP on the small G-protein Ras. Ras-GTP activates the protein kinase Raf, leading to the phosphorylation of MEK and ERK. Dyskinesia is attenuated in Ras-GRF1 knock out mice. A similar reduction is produced by inhibition of Ras, or MEK, achieved using lovastatin and SL327, respectively. ERK activation promotes the expression of the transcription factor ΔFosB, which is also implicated in LID. In addition, dyskinesia is associated to ERK-dependent activation of mTORC1, which is likely to accelerate local protein synthesis. Blockade of mTORC1 signaling with rapamycin has been found to reduce LID. See text for abbreviations.